Effective activation of the immune system in response to a pathogen depends on the ability of antigen presenting cells to deliver the necessary co-stimulatory (“danger”) signal in the context of antigen presentation. In mammals, this “adjuvant” effect is the result of the triggering of a family of germline-encoded receptors (Toll-like receptors, TLRs), which recognize a variety of conserved microbial and endogenous molecular structures. Activation of different TLRs elicits a proinflammatory response, which promotes the elimination of the pathogen via the activation of the innate arm of the immune system as well as determining the type of adaptive immune response (Th1 versus Th2 responses). Skewing between cellular or humoral immune effector function largely depends on the nature of the pathogenic insult and therefore on the specific array of TLRs that is activated.
In rational vaccine design (for example, for infectious disease prevention or cancer immunotherapy), manipulation of TLR activation is a desirable approach to developing synthetic immune activators (adjuvants) that can promote an appropriate response (i.e., cellular versus humoral). Conversely, hyperactivation of TLRs may lead to pathological situations in which the blockage of the receptor is desirable, for example, in some endotoxin-related conditions in which MD-2/TLR4, the signaling receptor complex for Gram-negative lipopolysaccharide, is activated.